Methods of treating muscle spasms using N-desmethylzopiclone

ABSTRACT

The invention is directed to compositions comprising, and methods of using, racemic N-desmethylzopiclone, optically pure (+)-N-desmethylzopiclone, and optically pure (−)-N-desmethylzopiclone in the treatment and prevention of diseases and conditions in mammals. The invention is further directed to novel methods of preparing N-desmethylzopiclone, optically pure (+)-N-desmethylzopiclone, and optically pure (−)-N-desmethylzopiclone.

1. FIELD OF THE INVENTION

[0001] The invention relates to compositions and methods for thetreatment and prevention of anxiety, convulsive disorders, and otherdisorders.

2. BACKGROUND OF THE INVENTION

[0002] Zopiclone, chemically named(±)-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4b]pyrazin-5-yl-4-methylpiperazine-1-carboxylate,is a non-benzodiazepine hypnotic which has the following structure:

[0003] Zopiclone and some of its uses are described by U.S. Pat. Nos.3,862,149 and 4,220,646. Uses of the optically pure (+) and (−)enantiomers of the drug (i.e., (+)-zopiclone and (−)-zopiclone) aredescribed by U.S. Pat. No. 5,786,357 and WO 93/10788, respectively.

[0004] Zopiclone binds at or near benzodiazepine receptor complexes.Goa, K. L. and Heel, R. C. Drugs, 32:48-65 (1986). These complexes arelocated both within the central nervous system and peripherally (e.g.,in the endocrine system), and contain macromolecular complexes whichcomprise benzodiazepine and GABA binding sites. Verma, A. and Snyder, S.H., Annu. Rev. Pharmacol. Toxicol. 29:307-22 (1989). Benzodiazepinereceptor complexes are further associated with, and interact with,membrane channels for chloride ion transport. Upon binding to abenzodiazepine receptor complex, zopiclone is believed to allostericallymodulate the activity of the complex by increasing trans-membraneconductance of chloride ions. This stabilizes neuronal membranepotentials and dampens excitatory input. See Meldrum, B. S., Brit. J.Clin. Pharm. 27(suppl. 1):3S-11S (1989); Goodman & Gilman's ThePharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p.365 (9^(th) ed., 1996).

[0005] Although chemically unrelated to the benzodiazepines, zopiclonepossesses a spectrum of activity analogous to that of thebenzodiazepines. Goa, K. L. and Heel, R. C. Drugs, 32:48-65, (1986).Zopiclone and its optically pure enantiomers are reportedly useful inthe treatment of diseases and conditions including, but not limited to,epilepsy, anxiety, aggressive behavior, muscle tension, behavioraldisorders, depression, schizophrenia, and endocrine disorders. See,e.g., WO 93/10787. Racemic zopiclone has been used to improve sleep inadults and geriatric patients with several types of sleep disordersincluding situational, transient primary and secondary insomnia. See,e.g., Brun, J. P., Pharm. Biochem. Behav. 29:831-832 (1988).

[0006] Some compounds which bind at benzodiazepine receptors can alsohave affinity for muscarinic receptors such as acetylcholine receptors.Julou, L., et al., Pharmacol. Biochem. Behav. 23:653-659 (1985).Consequently, administration of such compounds can result in adverseeffects caused by muscarinic agonists and antagonists. Such adverseeffects include, but are not limited to, drymouth, thirst, slowing andacceleration of the heart, dilated pupils, blurred vision, restlessness,fatigue, headache, hallucinations and delirium. Goodman & Gilman 's ThePharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p.142 (9^(th) ed., 1996).

[0007] The metabolism of zopiclone is rapid and complex. Whenadministered orally to healthy humans, the racemic drug is extensivelymetabolized by at least three major pathways, as shown below in Scheme1.

[0008] Metabolic pathways include oxidation, hydrolysis, anddemethylation. An oxidation pathway produces N-oxidezopiclone, ametabolite which is reportedly less active than zopiclone and reportedlyaccounts for 11% of an oral dose of racemic zopiclone. A hydrolysispathway produces an alcohol which is reportedly biologically inactive. Ademethylation metabolic pathway produces N-desmethylzopiclone, ametabolite which reportedly accounts for 15% of an oral dose of racemiczopiclone, and which is also reportedly inactive. Goa, K. L. and Heel,R. C. Drugs, 32:48-65, (1986). Additional metabolites are formed fromeach of the three pathways shown in Scheme 1.

[0009] The full pharmacological activity of zopiclone is reportedly dueto the drug itself and the N-oxide metabolite (i.e., N-oxidezopiclone).Id. Unfortunately, the single-dose elimination half-lives of both ofthese compounds after administration of racemic zopiclone range fromonly about 3.5 to about 6 hours, which limits the usefulness ofzopiclone in the treatment of a wide number of disorders. For example,the rapid elimination of zopiclone and N-oxidezopiclone limits theirusefulness in long-term anxiolytic treatment. The single-doseelimination half-life of the reportedly inactive N-desmethyl-zopiclonemetabolite (herein referred to as “N-desmethylzopiclone”) afteradministration of racemic zopiclone is between about 7 and about 11hours in healthy subjects. Id.

[0010] Racemic zopiclone possesses further disadvantages, in particular,it causes adverse side effects which include, but are not limited to,the development of a bitter taste due to salivary secretion of the drug,dry mouth, heart palpitations, drowsiness, morning tiredness, headache,dizziness, impairment of psychomotor skills and related effects. Acompound is thus desired for the treatment or prevention of variousdisorders which does not possesses disadvantages associated with racemiczopiclone.

3. SUMMARY OF THE INVENTION

[0011] The invention is directed to compositions comprising, and methodsof using, racemic N-desmethylzopiclone ((±)-N-desmethylzopiclone),optically pure (+)-N-desmethylzopiclone, and optically pure(−)-N-desmethylzopiclone in the treatment and prevention of diseases andconditions in mammals.

[0012] One embodiment of the invention encompasses a method of treatingor preventing anxiety in a patient which comprises administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of N-desmethylzopiclone or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. One method ofthis embodiment is the treatment or prevention of acute anxiety. Anothermethod of this embodiment is the treatment or prevention of chronicanxiety. Yet another method of this embodiment is the treatment orprevention of general anxiety disorder. In a preferred method of thisembodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclonesubstantially free of its (−) enantiomer.

[0013] Another embodiment of the invention encompasses a method oftreating or preventing a convulsive state in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. A particular method of this embodiment is the treatment orprevention of epilepsy or epileptic seizures. In a preferred method ofthis embodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclonesubstantially free of its (−) enantiomer.

[0014] Yet another embodiment of the invention encompasses a method oftreating or preventing an affective disorder in a patient whichcomprises administering to a patient in need of such treatment orprevention a therapeutically effective amount of N-desmethylzopiclone ora pharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. A particular method of this embodiment is the treatment orprevention of depression. Another method of this embodiment is thetreatment or prevention of attention deficit disorder or attentiondeficit disorder with hyperactivity. In a preferred method of thisembodiment, N-desmethylzopiclone is (+)-N-desmethylzopiclonesubstantially free of its (−) enantiomer.

[0015] A further embodiment of the invention encompasses a method oftreating or preventing a sleep disorder in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. A particular method of this embodiment is the treatment orprevention of insomnia. In a preferred method of this embodiment,N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free ofits (−) enantiomer.

[0016] Another embodiment of the invention encompasses a method oftreating or preventing aggressive behavior in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. In a preferred method of this embodiment, N-desmethylzopicloneis (+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

[0017] Still another embodiment of the invention encompasses a method oftreating or preventing spasticity or acute muscle spasm spasticity in apatient which comprises administering to a patient in need of suchtreatment or prevention a therapeutically effective amount ofN-desmethylzopiclone or a pharmaceutically acceptable salt, solvate,hydrate, or clathrate thereof. In a preferred method of this embodiment,N-desmethylzopiclone is (+)-N-desmethylzopiclone substantially free ofits (−) enantiomer.

[0018] Yet another embodiment of the invention encompasses a method oftreating or preventing a behavioral disorder in a patient whichcomprises administering to a patient in need of such treatment orprevention a therapeutically effective amount of N-desmethylzopiclone ora pharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. In a preferred method of this embodiment, N-desmethylzopicloneis (+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

[0019] Still another embodiment of the invention encompasses a method oftreating a schizophrenic disorder in a patient which comprisesadministering to a patient in need of such treatment or prevention atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. In a preferred method of this embodiment, N-desmethylzopicloneis (+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

[0020] Still another embodiment of the invention encompasses a method oftreating or preventing a disease or condition associated with abnormalplasma hormone levels in a patient which comprises administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of N-desmethylzopiclone or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. In a particularmethod of this embodiment, the disorder is an endocrine disorder. In apreferred method of this embodiment, N-desmethylzopiclone is(+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

[0021] Still another embodiment of the invention encompasses a method oftreating alcohol or drug addiction in a patient which comprisesadministering to a patient in need of such treatment a therapeuticallyeffective amount of N-desmethylzopiclone or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. In a preferredmethod of this embodiment, N-desmethylzopiclone is(+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

[0022] Still another embodiment of the invention encompasses a method oftreating or preventing drug withdrawal, alcohol withdrawal, symptoms ofdrug withdrawal, or symptoms of alcohol withdrawal in a patient whichcomprises administering to a patient in need of such treatment atherapeutically effective amount of N-desmethylzopiclone or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof. Examples of such symptoms are disclosed herein. In a preferredmethod of this embodiment, N-desmethylzopiclone is(+)-N-desmethylzopiclone substantially free of its (−) enantiomer.

[0023] Patients who may receive the therapeutic or prophylactic benefitsof the methods of the invention include those suffering from thediseases or conditions described above, as well as patients sufferingfrom cancer, patients currently being treated with a muscarinicantagonist or a muscarinic agonist, and patients who are susceptible toadverse effects associated with racemic zopiclone.

[0024] A further embodiment of the invention encompasses pharmaceuticalcompositions comprising N-desmethylzopiclone, or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. In preferredpharmaceutical compositions, N-desmethylzopiclone is(+)-N-desmethylzopiclone substantially free of its (−) enantiomer.Typical pharmaceutical compositions of the invention will compriseN-desmethylzopiclone and a pharmaceutically acceptable carrier. In oneembodiment, the pharmaceutical compositions of the present invention arefree of lactose (lactose-free), or other mono- or disaccharides. Inanother alternative embodiment, pharmaceutical compositions of theinvention are anhydrous or anhydrous and lactose-free.

[0025] Also encompassed by the invention are single unit dosage forms ofracemic and optically pure enantiomers of N-desmethylzopiclone, orpharmaceutically acceptable salts, solvates, hydrate, or clathratesthereof. Single unit dosage forms of the invention are suitable fororal, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal),parenteral (e.g., subcutaneous, intravenous, bolus injection,intramuscular, or intraarterial), or transdermal administration.Preferred single unit dosage forms of racemic and optically pure (+)- or(−)-N-desmethylzopiclone are suitable for oral administration. Mostpreferred single unit dosage forms of racemic and optically pure (+)- or(−)-N-desmethylzopiclone are tablets, capsules and caplets.

[0026] Another embodiment of the invention encompasses methods ofpreparing optically pure enantiomers of N-desmethylzopiclone. One methodcomprises treating an optically pure enantiomer of zopiclone with1-chloroethyl chloroformate. Another method comprises treating anoptically pure enantiomer of zopiclone with an azodicarboxylate, andhydrolyzing the resulting product under mild conditions. A preferredazodicarboxylate is diethyl azodicarboxylate. Yet another method of thisembodiment comprises resolution of racemic desmethylzopiclone usingL-N-benzyloxycarbonyl phenylalanine (L-ZPA) as a resolution reagent.

4. DETAILED DESCRIPTION OF THE INVENTION

[0027] The invention relates to the synthesis, use, and pharmaceuticalcompositions of N-desmethylzopiclone which, until now, was believed topossess no pharmacological activity. The invention further relates tothe synthesis and use of optically pure (+)-N-desmethylzopiclone andoptically pure (−)-N-desmethylzopiclone. A general aspect of theinvention encompasses the use of (±)-N-desmethylzopiclone or opticallypure enantiomers of N-desmethylzopiclone to treat or prevent diseasesand conditions which are affected by the modulation of one or morecentral or peripheral benzodiazepine receptors.

[0028] Surprisingly, N-desmethylzopiclone, which has been reported to bepharmacologically inactive, is in fact a benzodiazepine receptoragonist. In addition, racemic and optically pure N-desmethylzopicloneonly weakly antagonize muscarinic receptors Thus, racemicN-desmethylzopiclone or an optically pure enantiomer ofN-desmethylzopiclone may be used in the treatment or prevention of adisease or condition which is affected by the modulation of one or morebenzodiazepine receptors. Further, racemic and optically pureenantiomers of N-desmethylzopiclone may be used in the treatment orprevention of such diseases and conditions while avoiding longsingle-dose elimination half-life and adverse effects associated withracemic zopiclone. Further still, racemic and optically pure enantiomersof N-desmethylzopiclone may be used in the treatment or prevention ofsuch diseases and conditions while avoiding adverse effects associatedwith muscarinic receptor antagonists.

[0029] As used herein, the terms “mammal” and “patient” are usedinterchangeably, and include human.

[0030] The term “substantially free of its (−) enantiomer,” as usedherein, means that the composition contains a significantly greaterproportion of the (+) enantiomer of N-desmethylzopiclone in relation tothe (−) enantiomer of N-desmethylzopiclone. In a preferred embodiment ofthe present invention the term “substantially free of its (−)enantiomer,” as used herein, means that the composition contains atleast about 90% by weight of (+)-N-desmethylzopiclone and about 10% byweight or less of (−)-N-desmethylzopiclone. In a more preferredembodiment of the present invention, the term “substantially free of its(−) enantiomer,” as used herein, means that the composition contains atleast about 95% by weight of (+)-N-desmethylzopiclone and about 5% byweight or less of (−) N-desmethylzopiclone. In the most preferredembodiment, the term “substantially free of its (−) enantiomer,” as usedherein, means that the composition contains at least about 99% by weightof (+)-N-desmethylzopiclone and about 1% or less of(−)-N-desmethylzopiclone. In another preferred embodiment, the term“substantially free of its (−) enantiomer,” as used herein, means thatthe composition contains nearly 100% by weight of the (+) isomer ofN-desmethylzopiclone. The above percentages are based on the totalamount of N-desmethylzopiclone present in the composition. The terms“substantially optically pure (+)-N-desmethylzopiclone,” “optically pure(+)-N-desmethylzopiclone” and “(+) isomer of N-desmethylzopiclone” arealso encompassed by the above described amounts.

[0031] The term “substantially free of its (+) enantiomer,” as usedherein, means that the composition contains a significantly greaterproportion of the (−) enantiomer of N-desmethylzopiclone in relation tothe (+) enantiomer of N-desmethylzopiclone. In a preferred embodiment ofthe present invention the term “substantially free of its (+)enantiomer,” as used herein, means that the composition contains atleast about 90% by weight of (−)-N-desmethylzopiclone and about 10% byweight or less of (+)-N-desmethylzopiclone. In a more preferredembodiment of the present invention the term “substantially free of its(+) enantiomer,” as used herein, means that the composition contains atleast about 95% by weight of (−)-N-desmethylzopiclone and about 5% byweight or less of (+)-N-desmethylzopiclone. In the most preferredembodiment, the term “substantially free of its (+) enantiomer,” as usedherein, means that the composition contains at least about 99% by weightof (−)-N-desmethylzopiclone and about 1% or less of(+)-N-desmethylzopiclone. In another preferred embodiment, the term“substantially free of its (+) enantiomer,” as used herein, means thatthe composition contains nearly 100% by weight of the (−) isomer ofN-desmethylzopiclone. The above percentages are based on the totalamount of N-desmethylzopiclone present in the composition. The terms“substantially optically pure (−)-N-desmethylzopiclone,” “optically pure(−)-N-desmethylzopiclone” and “(−) isomer of N-desmethylzopiclone” arealso encompassed by the above described amounts.

[0032] As used herein, the term “pharmaceutically acceptable salt”refers to salts prepared from pharmaceutically acceptable non-toxicacids, including inorganic acids and organic acids. Suitable non-toxicacids include inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic,galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and thelike. Particularly preferred are hydrochloric, hydrobromic, phosphoric,and sulfuric acids, and most particularly preferred is the hydrochloridesalt.

[0033] As used herein, the term “benzodiazepine receptor agonist” meansa compound that mimics the in vitro binding activity of a benzodiazepine(e.g., diazepam) to central or peripheral benzodiazepine receptors. Asused herein, a benzodiazepine receptor agonist may exhibit full orpartial agonistic effects as defined by Goodman & Gilman 's ThePharmacological Basis of Therapeutics, Hardman, J. G., et al., eds. p.364 (9^(th) ed., 1996). Simply because a compound is referred to hereinas a “benzodiazepine receptor agonist,” however, does not imply that itexhibits a mechanism of action, a site of action, or an induced receptorconformational change identical to that of a benzodiazepine.

[0034] As used herein, the terms “diseases and conditions which areaffected by the modulation of one or more central or peripheralbenzodiazepine receptors,” “diseases and conditions which are affectedby the modulation of one or more benzodiazepine receptors,” and “diseaseor condition affected by the modulation of a benzodiazepine receptor”mean a disease or condition that has at least one symptom which ismitigated or alleviated by allosteric binding of a compound tobenzodiazepine receptors. Preferably, the at least one symptom ismitigated or alleviated by an increase in the trans-neuronal membranechloride current associated with the binding of only GABA tobenzodiazepine receptor complexes. Specific diseases and conditionswhich are affected by the modulation of one or more benzodiazepinereceptors include, but are not limited to: anxiety; affective disorderssuch as depression, attention deficit disorder (ADD), and attentiondeficit disorder with hyperactivity (ADDH) or attentiondeficit/hyperactivity disorder (ADHD); convulsive disorders such asepilepsy; aggressive behavior; spasticity or acute muscle spasm;behavioral disorders such as mood anxiety and schizophrenia; sleepdisorders such as insomnia; alcohol and drug addiction; and disordersassociated with abnormal plasma hormone levels such as endocrinedisorders.

[0035] As used herein, the terms “treating or preventing anxiety” and“treatment and prevention of anxiety” mean reducing the severity ofsymptoms associated with acute anxiety, chronic anxiety, general anxietydisorder caused by psychologic and/or physiologic factors, and otheranxiety disorders such as panic disorders, mood anxiety, panic attacks,phobias, obsessive-compulsive disorders, and post traumatic distressdisorder. Symptoms associated with acute anxiety include, but are notlimited to, a fear of losing control of one's own actions, a sense ofterror arising from no apparent reason, and a dread of catastrophe.Symptoms associated with chronic anxiety include, but are not limitedto, uneasiness, nervousness, nagging uncertainty about future events,headache, fatigue, and subacute autonomic symptoms.

[0036] As used herein, the terms “treating or preventing an affectivedisorder” and “treatment and prevention of an affective disorder” meanreducing the severity of symptoms associated with a psychologicaldisorder characterized by abnormality of emotional state, including butnot limited to, depression, dysthymia, attention deficit disorder,attention deficit disorder with hyperactivity, bipolar disorders,bipolar and manic conditions, and the like. The terms “attention deficitdisorder” (ADD) and “attention deficit disorder with hyperactivity”(ADDH), or “attention deficit/hyperactivity disorder” (AD/HD), are usedherein in accordance with the accepted meanings as found in theDiagnostic and Statistical Manual of Mental Disorders, 4^(th) Ed.,American Psychiatric Association (1997) (DSM-IV™).

[0037] As used herein, the terms “treating or preventing depression” and“treatment and prevention of depression” mean reducing the severity ofsymptoms associated with depression which include, but are not limitedto, changes in mood, feelings of intense sadness, despair, mentalslowing, loss of concentration, pessimistic worry, agitation, andself-deprecation. Symptoms associated with depression may also bephysical symptoms, which include, but are not limited to, insomnia,anorexia, weight loss, decreased energy and libido, and abnormalhormonal circadian rhythms.

[0038] As used herein, the terms “treating or preventing a convulsivestate” and “treatment and prevention of a convulsive state” meanreducing the severity and/or frequency of symptoms associated withconvulsive states which include, but are not limited to, recurrent,sudden, and often brief alterations of consciousness, motor activity,sensory phenomena, and autonomic responses which are often characterizedby convulsive seizures and/or tonic or clonic jerking of theextremities. The term “convulsive state” encompasses epilepsy andspecific types of epileptic seizures including, but not limited to,Tonic-clonic (Grand Mal), Partial (Focal) seizures, psychomotor (Complexpartial) seizures, pyknoepileptic or Absence (Petit Mal) seizure, andMyoclonic seizures.

[0039] As used herein, the terms “treating or preventing sleepdisorders” and “treatment and prevention of sleep disorders” meanreducing the severity of symptoms associated with sleep disorders suchas insomnia, insomnia of a primary nature with little apparentrelationship to immediate somatic or psychic events, and insomnia whichis secondary to some acquired pain, anxiety or depression. Symptomsassociated with sleep disorders include, but are not limited to,difficulty in sleeping and disturbed sleep patterns.

[0040] As used herein, the terms “treating or preventing aggressivebehavior” and “treatment and prevention of aggressive behavior” meanreducing the frequency and/or severity of manifestations of aggressivebehavior which include, but are not limited to, aggressive or sociallyinappropriate vocal outbursts and acts of physical violence.

[0041] As used herein, the terms “treating or preventing spasticity,”“treatment and prevention of spasticity,” “treating or preventingspasticity and acute muscle spasm,” and “treatment and prevention ofspasticity and acute muscle spasm” include reducing the severity ofsymptoms associated with a range of abnormalities of skeletal muscleregulation that result from problems of the nervous system. Apredominant symptom is heightened muscle tone or hyper-excitability oftonic stretch muscle reflexes. Symptoms of acute muscle spasm include,but are not limited to, trauma, inflammation, anxiety, and pain.

[0042] As used herein, the terms “treating or preventing a behavioraldisorder” and “treatment and prevention of a behavioral disorder” meanreducing or relieving from the symptoms of a behavioral disorder, whichinclude, but are not limited to, a subjective sense of terror, a dreadof catastrophe, uneasiness, nervousness, uncertainty, headache, fatigue,disturbed thinking, inappropriate effect, auditory hallucinations, andaggressive outbursts.

[0043] As used herein, the terms “treating or preventing a schizophrenicdisorder” and “treatment and prevention of a schizophrenic disorder”mean reducing the severity of symptoms associated with schizophrenicdisorders. Symptoms of schizophrenic disorders include, but are notlimited to, psychotic symptoms of disturbed thinking, feeling andgeneral behavior. Specific symptoms of schizophrenic disorders includethe inability to form clear, goal-directed thought, and emotionalchanges such as blunting and inappropriate affect. Other symptoms ofschizophrenic disorders include auditory hallucinations, delusions ofpersecution, threats of violence, minor aggressive outbursts, aggressivebehavior, disturbances of movement such as significant overactivity andexcitement, and retardation and stupor.

[0044] As used herein, the terms “treating or preventing a diseaseassociated with abnormal plasma hormone levels” and “treatment andprevention of a disease associated with abnormal plasma hormone levels”mean reducing the symptoms of diseases or conditions related to abnormalplasma levels of hormones including, but not limited to, growth hormone,ACTH, prolactin, luteinizing hormone, and other adrenocortical andtesticular hormones. The term “disease associated with abnormal plasmahormone levels” encompasses endocrine disorders such as, but not limitedto, growth hormone deficiency, gonadotropin deficiency, Cushing'ssyndrome, Grave's disease, hypothyroidism, and Addison's disease.

[0045] As used herein, the term “treating alcohol or drug addiction”means reducing the symptoms of disease or conditions related to alcoholor drug addiction including, but not limited to, drug or alcoholaddiction or symptoms of withdrawal from alcohol or drugs. Symptoms ofwithdrawal include, but are not limited to, depression, pain, fever,restlessness, lacrimation, rhinorrhea, uncontrollable yawning,perspiration, piloerection, restless sleep, mydriasis, twitching andmuscle spasms, severe aches in the back, abdomen and legs, abdominal andmuscle cramps, hot and cold flashes, insomnia, nausea, vomiting,diarrhea, coryza and severe sneezing, and increases in body temperature,blood pressure, respiratory rate, and heart rate.

4.1. SYNTHESIS AND PREPARATION

[0046] Racemic N-desmethylzopiclone is readily prepared from zopicloneusing an appropriate N-dealkylation reaction. Zopiclone may be preparedaccording to the method disclosed by U.S. Pat. Nos. 3,862,149 and4,220,646, both of which are incorporated herein by reference. Opticallypure (+) or (−) N-desmethylzopiclone can be prepared by resolution ofracemic desmethylzopiclone as described herein.

[0047] One way of preparing N-desmethylzopiclone enantiomers utilizes achiral carbonate, as outlined in Scheme 2:

[0048] wherein R is alkyl or vinyl. The carbonate can be resolved usingcertain lipases. Only one enantiomer can be prepared using this method,however, as the hydrolyzed chiral alcohol suffers a spontaneousracemization in the reaction medium, as shown in Scheme 3:

[0049] It has thus been found that a more efficient method of producingoptically pure enantiomers of N-desmethylzopiclone (i.e.,(+)-N-desmethylzopiclone and (−)-N-desmethylzopiclone) is from zopicloneitself. Two general approaches to this method have been discovered. Inthe first, racemic zopiclone ((±)-zopiclone) is resolved to the desiredenantiomer, and the undesired enantiomer is recycled using for example abase such as, but not limited to, DBU. This is shown in Scheme 4:

[0050] According to this approach, zopiclone is resolved using methodssuch as chiral chromatography, although the use of one or more chiralacids, such as malic acid, mandalic acid, and DBTA, is preferred. See,e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions,(Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds(McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents andOptical Resolutions p. 268 (E. L. Eliel, Ed. Univ. of Notre Dame Press,Notre Dame, Ind., 1972). When preparing optically pure isomers ofzopiclone using these methods, Applicants have found that the resolutionprocess is preferably performed using higher amounts of the chiral acid.

[0051] For example, this method could be used to prepare optically pure(+)-N-desmethylzopiclone, and the (−) enantiomer in the mother liquorcould be racemized under basic conditions (e.g. with a tertiary amine)to reform (±)-zopiclone. However, since it has been discovered thatzopiclone is not very stable under these conditions and that(±)-zopiclone is thus recovered from the undesired enantiomer in lowyields, an alternative route for the recycling of the other enantiomeris outlined in Scheme 5:

[0052] A second approach of obtaining an optically pure enantiomer ofzopiclone has accordingly been developed, and is shown in Scheme 6:

[0053] wherein R is methyl. According to this method, a commerciallyavailable alcohol precursor of zopiclone is treated with chiralauxiliary-based chloroformate to yield one major stereoisomer of thecarbonate product. Referring to Scheme 6, R* is preferably a common,inexpensive chiral alcohol such as, but not limited to menthol, or achiral aminoalcohol such as, but not limited to glycinol andaminoindanol. A particular advantage of this method is that it requiresno recycling of an undesired enantiomer, yet allows recycling of thechiral auxiliary.

[0054] In another embodiment of this method, the chiral auxiliary isreplaced with an enzyme as outlined in Scheme 7:

[0055] wherein R is methyl and R′ is vinyl or 1-methylvinyl.

[0056] Another method useful in the production of optically pure(+)-N-desmethylzopiclone and optically pure (−)-N-desmethylzopiclonecomprises the use of chloroalkyl chloroformate followed by a strong baseor acid hydrolysis. See, e.g., Booher, R. N. and Pohland, A., J. Med.Chem. 20(8):1065-1068 (1977). As mentioned above, however, zopiclone andN-desmethylzopiclone tend to decompose when treated with strong base oracid. Another method comprises treating zopiclone with anazodicarboxylate and hydrolyzing the resulting product under mildconditions, as shown in Scheme 8:

[0057] According to this method, the azodicarboxylate is preferablyselected from the group consisting of diethyl azodicarboxylate,di-tert-butyl azodicarboxylate, and di-trichloromethyl azodicarboxylate.More preferably, the azodicarboxylate is diethyl azodicarboxylate ordi-tert-butyl azodicarboxylate. In one embodiment, the hydrolyzing agentis a mixture of ethanol and NH₄Cl. Suitable solvents include toluene orother solvents of a secular nature.

[0058] A preferred method of preparing an optical isomer ofN-demethylzopiclone, e.g., (S)-demethylzopiclone, is illustrated inScheme 9.

[0059] According to this method optically pure (S)-zopiclone iscontacted with α-chloroethyl chloroformate in a suitable solvent suchas, but not limited to, CH₃CN to form the corresponding quaternary aminesalt. See generally, Olofson, R. A. and Martz, T. J. J. Org. Chem.,49:2081 (1984). Methanolysis of the quaternary amine salt gives thehydrochloride salt of (S)-desmethylzopiclone in high yield. Thehydrochloride salt can be isolated by filtration and the reactionby-products are removed. Purification of the crude reaction product(e.g., by recrystallization) affords pure (S)-desmethylzopiclonehydrochloride.

[0060] An advantage of this process is that methanolysis releases theproduct as the hydrochloride salt, which precipitates out from thereaction system. The isolation is straight forward, requiring simplefiltration, and al reaction by-products, including CH₃Cl, CO₂, andCH₃CH(OMe)₂, are volatile and easily removed during the process.

[0061] Yet another preferred method of preparing optically pure isomersof N-desmethylzopiclone, e.g., (S)-desmethylzopiclone, is shown inScheme 10. According to this method racemic desmethylzopiclone isresolved using a suitable resolution agent such as, but not limited to,L-N-benzyloxycarbonyl phenyl alanine (L-ZPA). Racemic desmethylzopiclonecan be prepared, for example, by methods disclosed in U.S. Pat. Nos.3,862,149 and 4,220,646.

[0062] Isolation and purification of N-desmethylzopiclone is preferablydone using chromatography, preferably column chromatography, and morepreferably high performance liquid chromatography (HPLC). Other methods,such as isolation by evaporation of the solvent, followed byrecrystallization, may also be employed.

4.2. PHARMACEUTICAL COMPOSITIONS AND METHOD OF USE

[0063] The magnitude of a prophylactic or therapeutic dose of an activeingredient of the invention (i.e., (±)-N-desmethylzopiclone, opticallypure (+)-N-desmethylzopiclone, and optically pure(+)-N-desmethylzopiclone) in the acute or chronic management of thediseases or conditions recited herein will vary with the nature andseverity of the disease or condition.

[0064] The magnitude of a prophylactic or therapeutic dose of an activeingredient of the invention (i.e., (±)-N-desmethylzopiclone, opticallypure (+)-N-desmethylzopiclone, or optically pure(−)-N-desmethylzopiclone) will also vary according to the route by whichthe active ingredient is administered. The dose, and perhaps the dosefrequency, will also vary according to the age, body weight, andresponse of the individual patient. Suitable dosing regimens can bereadily selected by those skilled in the art with due consideration ofsuch factors. In general, the recommended daily dose range for theconditions described herein lie within the range of from about 0.1 mg toabout 500 mg per day, given as a single once-a-day dose, or as divideddoses from 2 to 4 times throughout the day. Preferably, a daily doserange should be from about 0.5 mg to about 250 mg per day, morepreferably, between about 1 mg and about 200 mg per day. In managing thepatient, the therapy should be initiated at a lower dose, perhaps about0.1 mg to about 25 mg, and increased if necessary up to about 1 mg toabout 200 mg per day as either a single dose or divided doses, dependingon the patient's global response.

[0065] It may be necessary to use dosages of the active ingredientoutside the ranges disclosed herein in some cases, as will be apparentto those of ordinary skill in the art. Because elimination of zopiclonemetabolites from the bloodstream is dependant on renal and liverfunction, it is recommended that the total daily dose be reduced by atleast about 50% in patients with moderate hepatic impairment, and thatit be reduced by about 25% in patients with mild to moderate renalimpairment. For patients undergoing hemodialysis, it is recommended thatthe total daily dose be reduced by about 5% and that the dose bewithheld until the dialysis treatment is completed. Furthermore, it isnoted that the clinician or treating physician will know how and when tointerrupt, adjust, or terminate therapy in conjunction with individualpatient response.

[0066] The phrase “therapeutically effective amount” as used herein withrespect to the treatment or prevention of diseases and conditionsencompasses the above described dosage amounts and dose frequencyschedules. Different therapeutically effective amounts may be applicablefor different diseases and conditions, as will be readily known by thoseof ordinary skill in the art. Similarly, amounts sufficient to treat orprevent such disorders, but insufficient to cause adverse effectsassociated with zopiclone, are also encompassed by the above describeddosage amounts and dose frequency schedules.

[0067] Any suitable route of administration may be employed forproviding the patient with an effective dosage of racemic or opticallypure (+)- or (−)-N-desmethylzopiclone. Suitable routes include, but arenot limited to, oral, mucosal (e.g., nasal, sublingual, vaginal, buccalor rectal), parenteral (e.g., subcutaneous, intravenous, bolusinjection, intramuscular, or intraarterial), transdermal, and.

[0068] The pharmaceutical compositions of the invention compriseN-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate,hydrate, or clathrate thereof as an active ingredient, and may alsocontain a pharmaceutically acceptable carrier and optionally othertherapeutic ingredients known to those skilled in the art. Preferredpharmaceutical compositions comprise optically pure(+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt,solvate, hydrate, or clathrate thereof.

[0069] Compositions of the invention are suitable for oral, mucosal(e.g., nasal, vaginal, or rectal), parenteral (e.g., subcutaneous,intravenous, bolus injection, intramuscular, or intraarterial),sublingual, transdermal, or buccal administration, although the mostsuitable route in any given case will depend on the nature and severityof the condition being treated. The compositions may be convenientlypresented in unit dosage form and prepared by any of the methods wellknown in the part of pharmacy. Dosage forms include tablets, caplets,troches, lozenges, dispersions, suspensions, suppositories, solutions,capsules, soft elastic gelatin capsules, patches, and the like.Preferred dosage forms are suitable for oral administration.

[0070] In practical use, racemic or optically pure (+)- or(−)-N-desmethylzopiclone can be combined as the active ingredient inintimate admixture with a pharmaceutically acceptable carrier accordingto conventional pharmaceutical compounding techniques. The carrier maytake a wide variety of forms and comprises a number of componentsdepending on the form of preparation desired for administration. Thecompositions of the invention include, but are not limited to,suspensions, solutions and elixirs; aerosols; or excipients, including,but not limited to, starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegratingagents, and the like. Preferably, the pharmaceutical composition is inthe form of an oral preparation.

[0071] Pharmaceutical compositions of the invention suitable for oraladministration may be presented as discrete pharmaceutical unit dosageforms, such as capsules, cachets, soft elastic gelatin capsules,tablets, caplets, or aerosols sprays, each containing a predeterminedamount of the active ingredients, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any method known in the art of pharmacywhich comprises the step of bringing an active ingredient intoassociation with a carrier. In general, the compositions are prepared byuniformly and intimately admixing the active ingredients with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product into the desired presentation. Oral solidpreparations are preferred over oral liquid preparations. Preferred oralsolid preparations are capsules and tablets.

[0072] A tablet may be prepared by compression or molding techniques.Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form, such as powder orgranules, optionally mixed with one or more pharmaceutically acceptableexcipients, such as a binder, lubricant, inert diluent, granulatingagent, surface active or dispersing agent, or the like. Molded tabletsmay be made by molding, in a suitable machine, a mixture of the powderedcompound moistened with an inert liquid diluent. Preferably, eachtablet, cachet, caplet, or capsule contains from about 0.1 mg to 500 mg,more preferably from about 0.5 mg to about 250 mg, and most preferablybetween about 1 mg and about 200 mg.

[0073] Pharmaceutical compositions of the invention may also beformulated as a pharmaceutical composition in a soft elastic gelatincapsule unit dosage form by using conventional methods well known in theart. See, e.g., Ebert, Pharm. Tech, 1(5):44-50 (1977). Soft elasticgelatin capsules have a soft, globular gelatin shell somewhat thickerthan that of hard gelatin capsules, wherein a gelatin is plasticized bythe addition of plasticizing agent, e.g., glycerin, sorbitol, or asimilar polyol. The hardness of the capsule shell may be changed byvarying the type of gelatin used and the amounts of plasticizer andwater. The soft gelatin shells may contain a preservative, such asmethyl- and propylparabens and sorbic acid, to prevent the growth offungi. The active ingredient may be dissolved or suspended in a liquidvehicle or carrier, such as vegetable or mineral oils, glycols, such aspolyethylene glycol and propylene glycol, triglycerides, surfactants,such as polysorbates, or a combination thereof.

[0074] A pharmaceutically acceptable excipient used in the compositionsand dosage form of the invention may be a binder, a filler, or a mixturethereof. A pharmaceutically acceptable excipient may also include alubricant, a disintegrant, or mixtures thereof. One embodiment of theinvention encompasses a pharmaceutical composition which issubstantially free of all mono- or di-saccharide excipients. Anotherembodiment encompasses a pharmaceutical composition which is free oflactose.

[0075] Binders suitable for use in the compositions and dosage forms ofthe invention include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, or mixtures thereof.

[0076] Suitable forms of microcrystalline cellulose include, forexample, the materials sold as AVICEL-PH-101, AVICEL-PH-103 andAVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa., U.S.A.). An exemplary suitablebinder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581 by FMC Corporation.

[0077] Fillers suitable for use in the compositions and dosage forms ofthe invention include, but are not limited to, talc, calcium carbonate(e.g., granules or powder), lactose, microcrystalline cellulose,powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol,starch, pre-gelatinized starch, or mixtures thereof.

[0078] The binder/filler in pharmaceutical compositions of the inventionis typically present in about 50 to about 99 weight percent of thepharmaceutical composition.

[0079] Disintegrants are used to cause the tablet to disintegrate whenexposed to an aqueous environment. Too much of a disintegrant willproduce tablets which may disintegrate in the bottle due to atmosphericmoisture; too little may be insufficient for disintegration to occur andmay thus alter the rate and extent of release of the drug ingredient(s)from the dosage form. Thus, a sufficient amount of disintegrant that isneither too little nor too much to detrimentally alter the release ofthe drug ingredient(s) should be used to form dosage forms of racemicand optically pure (+)- or (−)-N-desmethylzopiclone made according tothe invention. The amount of disintegrant used varies based upon thetype of formulation and mode of administration, and is readilydiscernible to those of ordinary skill in the art. Typically, about 0.5to about 15 weight percent of disintegrant, preferably about 1 to about5 weight percent of disintegrant, may be used in the pharmaceuticalcomposition.

[0080] Disintegrants suitable for use in the compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums ormixtures thereof.

[0081] Lubricants suitable for use in the compositions and dosage formsof the invention include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of BaltimoreMd.), a coagulated aerosol of synthetic silica (marketed by Deaussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), or mixtures thereof A lubricant mayoptionally be added, typically in an amount of less than about 1 weightpercent of the pharmaceutical composition.

[0082] In addition to the common dosage forms set out above, thecompounds of the invention may also be administered by controlledrelease means or delivery devices that are well known to those ofordinary skill in the art, such as those described in U.S. Pat. Nos.:3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and5,733,566, the disclosures of which are each incorporated herein byexpress reference thereto. These pharmaceutical compositions can be usedto provide slow or controlled-release of one or more of the activeingredients therein using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, microspheres, or thelike, or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled-release formulations known tothose of ordinary skill in the art, including those described herein,may be readily selected for use with the pharmaceutical compositions ofthe invention. Thus, single unit dosage forms suitable for oraladministration, such as tablets, capsules, gelcaps, caplets, and thelike, that are adapted for controlled-release are encompassed by theinvention.

[0083] All controlled-release pharmaceutical products have a common goalof improving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations may include: 1) extended activity of the drug; 2) reduceddosage frequency; and 3) increased patient compliance. In addition,controlled-release formulations can be used to effect the time of onsetof action or other characteristics, such as blood levels of the drug,and thus may affect the occurrence of side effects.

[0084] Most controlled-release formulations are designed to initiallyrelease an amount of drug that promptly produces the desired therapeuticeffect, and gradually and continually release of other amounts of drugto maintain this level of therapeutic effect over an extended period oftime. In order to maintain this constant level of drug in the body, thedrug must be released from the dosage form at a rate that will replacethe amount of drug being metabolized and excreted from the body.

[0085] The controlled-release of an active ingredient may be stimulatedby various inducers, for example pH, temperature, enzymes, water, orother physiological conditions or compounds. The term“controlled-release component” in the context of the invention isdefined herein as a compound or compounds, including, but not limitedto, polymers, polymer matrices, gels, permeable membranes, liposomes,microspheres, or the like, or a combination thereof, that facilitatesthe controlled-release of the active ingredient.

[0086] Pharmaceutical compositions of the invention may also beformulated for parenteral administration by injection (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), and may be dispensed in a unit dosage form, such as amultidose container or an ampule. Such compositions for parenteraladministration may be in the form of suspensions, solutions, emulsions,or the like in aqueous or oily vehicles, and in addition to the activeingredients may contain one or more formulary agents, such as dispersingagents, suspending agents, stabilizing agents, preservatives, and thelike.

[0087] The invention is further defined by reference to the followingexamples describing in detail the preparation of the compositions of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the purpose and interest of this invention.

5. EXAMPLES Synthesis of N-Desmethylzopiclone

[0088] Racemic and optically pure enantiomers of N-desmethylzopiclonewere prepared according to the procedures provided below. It should benoted that X-ray crystal diffraction studies indicate that the absoluteconfiguration of both (+)-zopiclone and (+)-N-desmethylzopiclone is theS-configuration.

Example 1 Synthesis of (±)-N-Desmethylzopiclone

[0089] To a solution of (±)zopiclone (6.2 g, 20 mmol) in toluene (120ml) was added diethyl azodicarboxylate (DEAD, 8.2 g, 50.0 mmol) and thesolution was stirred at 60° C. for 26 hours. The solvent was removedunder reduced pressure. The residue was added to 60 ml of EtOH/NH₄Cl aq(1:1) and the resulting mixture was refluxed for 4 hours. The reactionmixture was concentrated to remove ethanol under reduced pressure andthe residue was partitioned by adding saturated NaHCO₃ solution andCH₂Cl₂ (100 ml). The organic phase was then separated and washed withwater (30 ml), brine (30 ml), and dried over NaSO₄. The crude productwas loaded onto a silica gel column and eluted with CH₃CN:MeOH:NH₄OH(25:4:1) to give 1.56 g of product with chemical purity of approximately91% (25% yield). A second flash chromatography yielded(±)-N-desmethylzopiclone with >98% chemical purity. ¹H NMR (CDCI₃),δ:2.4-3.8 (b, 8H), 7.7-7.82 (dd, 1H), 8.0 (s, 1H), 8.4 (s,1H), 8.5 (d,1H), 8.82-8.88 (dd, 2H), 2-6 (NH). ¹³C NMR δ:45.5, 45.9, 79.3, 116.3,128.5, 138.3, 144.1, 146.9, 148.0, 153.7, 155.8, 163.2.

Example 2 Synthesis of (+)-Zopiclone

[0090] (a) Preparation of (+)-Zopiclone-D-Malate Salt:

[0091] A three-neck 2.0 L flask was charged with (±)-zopiclone (40 g,0.101 mol, 1.0 eq), D-malic acid (13.4 g, 0.97 eq.), 406 mL MeOH and 754mL acetone. The reaction mixture was heated in an oil bath to 55-56° C.for about 30 min and gradually cooled to 45-47° C. over approximately 30min. (+)-zopiclone-D-malate seeds (0.1 g, 0.02%) was added at 45-47° C.The reaction mixture was cooled to 40° C. over 1 h and then cooled to10-15° C. over 3 h. Then the slurry was held at 10-15° C. for 30 min.The solid product was isolated by filtration and washed with cold MeOH(2×50 mL, 0-5° C.). The white product was dried at 30-40° C./28 mmHgover 6-12 h to give (+)-Zopiclone-D-malate (22.6 g, 42%, 96.5% ee).

[0092] (b) Preparation of(+)-Zopiclone:

[0093] A three-neck 250 mL flask was charged with (+)-zopiclone-D-malate(10 g, 93% ee), 20 mL water and 150 mL of EtOAc. The reaction mixturewas heated in an oil bath to 30-40° C. An aqueous K₂CO₃ solution (40%, 8g) was added slowly over 5 min. The mixture was then heated to 60-65° C.and the organic phase was isolated and washed with 100 mL water. Themixture was polish filtered, rinsed with EtOAc (20 mL) and concentratedto 70-80 mL. The resulting slurry was cooled and held for 2 h at 0-5° C.The crystal product was isolated by filtration and was washed with coldEtOAc (20 mL, 0-5° C.). The white product was dried at 30-40° C./28 mmHgover 6-12 h to give (+)-zopiclone (6.4 g, 86.2%, 99.9% ee).

Example 3 Synthesis of (+)-N-Desmethylzopiclone

[0094] To a solution of (+)-zopiclone (4.0 g, 10.3 mmol) in toluene (100ml) was added DEAD (5.4 g, 30.0 mmol) and the solution was stirred at55° C. for 40 hours. The solvent was removed under reduced pressure andthe residue was added 60 ml of EtOH/NH₄Cl aq (1:1) and the resultingmixture was refluxed for 4 hours. The reaction mixture was concentratedunder reduced pressure to remove the ethanol and the residue waspartitioned by adding saturated NaHCO₃ solution and CH₂Cl₂(100 ml). Theorganic phase was then washed with water (30 ml), brine (30 ml), anddried over Na2SO₄. The crude product was loaded onto a silica gel columnand eluted with CH₃CN:MeOH:NH₄OH (25:4:1) to give 1.25 g of the productwith chemical purity of ca 90% (27% yield). A second flashchromatography yielded (+)-N-desmethylzopiclone with >97% chemicalpurity and >99% ee by chiral HPLC: Chiralcel OD, mobile phase:Hexane:Ethanol:Methanol:DEA (55:15:30:0.1). Retention time: 11.6 minutesfor the (+) isomer and 14.7 minutes for (−) isomer. ([α]=+141 C=1,CDCl₃), ¹H NMR (CDCl₃), δ 2.4-3.8 (b, 8H), 7.7-7.82(dd, 1H), 8.0 (s,1H), 8.4 (s, 1H), 8.5 (d, 1H), 8.82-8.88 (dd, 2H), 2-6 (NH). ¹³C NMR δ:45.5, 45.9, 79.3, 116.3, 128.5, 138.3, 144.1, 146.9, 148.0, 153.7,155.8, 163.2.

Example 4 Synthesis of (−)-N-Desmethylzopiclone

[0095] (−)-Desmethylzopiclone was prepared from (−)-zopiclone accordingto the procedure described above. ([α]=−158, C=1, CDCl₃), ¹H NMR(CDCl₃), δ: 2.4-3.8 (b, 8H), 7.7-7.82 (dd, 1H), 8.0 (s, 1H), 8.4 (s,1H), 8.5 (d, 1H), 8.82-8.88 (dd, 2H), 2-6 (NH). ¹³C NMR, δ: 45.5, 45.9,79.3, 116.3, 128.5, 138.3, 144.1, 146.9, 148.0, 153.7, 155.8, 163.2.

Example 5 Preparation of (+)-Desmethylzopiclone Hydrochloride

[0096] (a) Demethylation:

[0097] To a 12 L reaction flask under Ar, were charged (+)-zopiclone(778 g, 2.0 mmol), ACN (4L) and 1-chloroethyl chloroformate (328.9 g,2.3 mol). The reaction mixture was heated at 73-75° C. for 6 h withstirring. MeOH (1.0 L) was added and the mixture was heated under areflux for 3-4 h. The reaction slurry was cooled to 5-10° C. for 2 h.The solid product was isolated via filtration, followed by washing withEtOH (200 mL×3) and toluene (200 mL×3). The final product was dried inan oven for 12 h (28 mm Hg) at 40-45° C. The isolated product (i.e.,crude (+)-desmethylzopiclone hydrochloride salt) was 610 g (74%).

[0098] (b) Recrystallization of (+)-Desmethylzopiclone Hydrochloride(DMZ):

[0099] To a 12 L reaction flask equipped with overhead stirrer underargon, were charged crude (+)-DMZ.HCI salt (450 g), EtOH (4.8 L) andwater (1.5 L). The reaction mixture was heated under reflux for 1 h, andthen cooled to 20° C. over 1 h. The resulting slurry was further cooledto 0-5° C. and stirred at that temperature for 1 h. The white solidproduct was isolated by filtration followed by washing with EtOH (500mL). The final product was dried in an oven for 12 h (28 mm Hg) at40-45° C. The isolated product was 377 g (84%). ¹H NMR (300 MHZ, DMSO),δ (ppm): 8.95 (dd, 2H, J=7.2, 3.0 Hz), ), 8.57 (d, 1H, J=7.2 Hz), 8.45(s, 1H), 8.10 (s, 1H), 7.80 (m, 1H), 3.60 (bro d, 2H), 3.25 (bro s, 2H),2.88 (bro s, 2H), 2.62 (bro s, 2H). MS 374 (M+).

[0100] The process was repeated and the results from both experimentsare summarized in Table 1 below. TABLE 1 Demethylation¹Recrystallization² Purity (HPLC Experiment Yield (%) HPLC A % Yield (%)assay %) 1 610 g (74) 99.74 377 g (84) 99.5 2 580 g (71) 99.34 485 g(86) 99.5

Example 6 Resolution of Racemic Desmethylzopiclone

[0101] This is an alternate method of preparing of optically pure(+)-desmethylzopiclone. Racemic desmethylzopiclone can be obtainedeither by the chloroformate demethylation method described in Example 5above using racemic zopiclone as the starting material, or by knownliterature methods.

[0102] (a) Identifying Resolution Agents:

[0103] A reagent screen was performed to identify an effectiveresolution agent for racemic N-desmethylzopiclone. The screen identifiedL-N-benzyloxycarbonyl phenyl alanine (L-ZPA) (available from SEMchemical) as an effective resolution agent for desmethylzopiclone andindicated that other acids suitable for resolution of zopiclone areineffective for the resolution of N-desmethylzopiclone. L-ZPA may alsobe used for the resolution of racemic zopiclone. Table 2 summarizes theexperimental results. TABLE 2 (±)- Desmethyl- Acid Comments Exp. #zopiclone (g) (g) Solvents Conditions and Yields 1 1.0 L-ZPA 40 70 mL 1.75-79° C. 1 h   80% ee,  0.8 (1 eq.) EtOH/7 mL 2. rt. for 2 h   33%yield water 2 10 L-ZPA EtOH/water 1. 75-79° C. 1 h   80% ee, 30.8 (1eq.) 2. rt. for 4 h   28% yield 3 8.0 L-ZPA EtOH/water 1. 75-79° C. 1 h  91% ee, 6.15 (1 eq.) 2. rt. for 12 h 31.4% yield 4 1.0 D-malic acid 20mL 1. 75-79° C. 1 h No crystals 0.36 (1 eq.) EtOH/2 mL water 2. rt. for14 h observed. 5 1.0 D-malic acid 20 mL 1. 75-79° C. 1 h No crystals0.36 (1 eq.) MeOH/2 mL water 2. rt. for 12 h observed. 6 1.0 D-DTTA 50mL 1. 75-79° C. 1 h 1. at room  1.0 (1 eq.) EtOH/5 mL water 2. rt. for2h with 80% ee. 2. Hold it for 1 h, 0% ee. 7 1.0 D-DTTA 50 mL 1. 75-79°C. 1 h Filtered at  1.0 (1 eq.) EtOH/5 mL water 2. 79° C. for 5 50° C.with min.   15% yield and 95.5% ee. 8 32 L-ZPA 1600 mL 1. 75-79° C. 1 h27.6% yield, 1.0 eq. EtOH/160 2. rt. for 14 h   96% ee mL water 3.reslurry in EtOH

[0104] Using L-ZPA, and a solvent mixture of EtOH and water highlyoptically enriched (typical>90% ee) (+)-desmethylzopiclone.L-ZPA saltwas isolated. The free base of (+)-desmethylzopiclone can be obtained bythe treatment of (+)-desmethylzopiclone.L-ZPA salt in EtOAc with K₂CO₃solution.

[0105] (b) Resolution of (±)-Desmethylzopiclone:

[0106] (±)-Desmethylzopiclone (8.0 g, 21.3 mmol) and 6.4 g L-ZPA (21.3,1 equiv.) were combined in 40 mL water and 400 mL EtOH. The mixture washeated to 75-78° C. for 1 h to form a clear solution. The mixture wascooled to 20° C. overnight. The solids were isolated and the cake waswashed with 150 mL EtOH. The wet cake was transferred into a 500 mLflask with 150 mL EtOH. The slurry was refluxed for 2 h. The slurry wascooled to 0-5° C. for 1 h. The solid product was isolated via filtrationand was washed with EtOH (25 mL). The final product was dried in an ovenfor 12 h (28 mm Hg) at 45-50° C. to give (+)-desmethylzopiclone-L-ZPAsalt (4.5 g, 31.4%, 91% ee).

Example 7 Determination of Biological Activity

[0107] A pharmacologic study is conducted to determine the relativepotency, comparative efficacy, and binding affinity ofN-desmethylzopiclone. The pharmacologic profile of hypnotic-sedative,anxiolytic agents of the benzodiazepine class is well established, andhas been extended to non-benzodiazepine agents of the cyclopyrroloneclass. See, e.g., Goodman & Gilman 's The Pharmacological Basis ofTherapeutics, Hardman, J. G., et al, eds. ch. 17, pp. 361-396 (9^(th)ed., 1996); Bardone, M. C., et al., Abstract No. 2319, 7^(th) Int.Congr. Pharm. Paris, (July, 1978: Pergamon Press, London); Julou, L. etal., Pharmacology, Biochemistry and Behavior, 23:653-659 (1985).

[0108] A variety of experimental models can be used to characterize thevarious activities of N-desmethylzopiclone, including itsanticonvulsant, myorelaxant, anti-aggressive, sedative-hypnotic, andanxiolytic (i.e., anti-anxiety) activities. In an examination of eachelement of the pharmacologic profile, N-desmethylzopiclone is comparedwith pharmacologic standards such as nitrazepam and diazepam in avariety of animal models. The dose (mg/kg) of each agent that is capableof inhibiting by 50% (the ID₅₀ or ED₅₀) an induced response in rodents,for example, provides the basis for comparison.Pentylenetetrazole-induced, picrotoxin convulsions, andelectrically-induced convulsions can thus be used to demonstrate theanti-convulsant activity of N-desmethylzopiclone. Haefely, W.,Psychotropic Agents, Hofmeister, F. and Stille, G., eds., part 11, pp.12-262 (Springer Verlag, Berlin: 1981). Further, in the rat, in theamygdala kindled model of epilepsy, daily electrical stimulation of theamygdala induces a progressive increase of epileptic afterdischargeduration, with increasing epileptic behavioral symptoms, producing inabout two weeks a generalized convulsive crisis. Presumably, previouslyineffective stimuli have sensitized neuronal pathways, and it has beensuggested that a similar mechanism may exist for the induction of ananxiety state in man after repeated stresses.

[0109] Similar models are available for determination of themyorelaxant, anti-aggressive, and sedative-hypnotic activities ofN-desmethylzopiclone in both mice and rats. See, Julou, L. et al.,Pharmacology, Biochemistry and Behavior, 23:653-659 (1985).

[0110] The pharmacologic activity of N-desmethylzopiclone may also becompared with benzodiazepines for its affinity for binding to both CNSand peripheral benzodiazepine receptors. In this biochemical affinitybinding study, the binding of ³H-radiolabeled N-desmethylzopiclone isstudied in a synaptosomal membrane preparation of cerebral tissue fromfemale rat brain. The tissue is preferably prepared by homogenization inice-cold isosmotic (0.32 M) sucrose, and centrifugation, first at lowspeed (1,000×g for 10 minutes), with the resultant supernatant solutionthen being centrifuged at high speed (48,000×g for 20 minutes). Theresulting pellet is suspended in Kreb-Tris buffer at pH 7.4, and theconcentration of protein is adjusted to 15 mg/ml. This synaptosomalmembrane preparation may be stored at −18° C. until used at roomtemperature (e.g., about 22° C.) with the radio-cyclopyrrolone inKreb-Tris buffer solution pH 7.4. Following a 30-minute incubation,separation of the bound and free drug is performed by centrifugation at1,000×g for 10 minutes in scintillation vials. The supernatant solutionis collected, the pellet is dissolved in a counting vehicle, and theradioactivity is counted using a liquid scintillation counter. Theoriginal supernatant solution from the first incubation, which containsunbound radiolabeled drug, may be used in additional binding studiesusing the same method. Additional controls involve, for instance, studyof the radioactivity bound in the presence of 10 μM flunitrazepam (abenzodiazepine), which experiment is useful in assessing non-specificbinding. Furthermore, the binding of various concentrations ofradiolabeled N-desmethylzopiclone in the presence of a fixedconcentration of GABA provides additional information as to themodulation of the GABA-ergic system by N-desmethylzopiclone. See,Jacqmin, P., et al., Arch. Int. Pharmacodyn, 282:26-32 (1986); Jacqmin,P., et al., J. Pharm. Belg. 40:35-54 (1985). With regard to peripheralbenzodiazepine receptors and their distinction from centralbenzodiazepine binding sites, see, e.g., Verma, A. and Snyder, S. H.,Ann. Rev. Pharmacol. Toxicol. 29:307-322 (1989), which is herebyincorporated by reference.

Example 8 Measured Biological Activity

[0111] The binding of N-desmethylzopiclone was determined at the centralbenzodiazepine receptor and at the non-selective muscarinic receptor,both of which were isolated from rat cerebral cortex. Compounds weretested initially at 10 μM in duplicate, and if at least a 50% inhibitionof specific binding was observed, they were tested further at 10different concentrations in duplicate in order to obtain fullcompetition curves. IC₅₀ values (concentration required to inhibit 50%specific binding) were determined by nonlinear regression analysis ofthe curves, and inhibition constants (K_(i)) were also calculated. Thesedata are provided below in Table 3. TABLE 3 Benzodiazepine MuscarinicCompound IC₅₀ and (K_(i)) Values (nM) (% Inhibition)(±)-N-desmethylzopiclone 1,100 10  (924) (+)-N-desmethylzopiclone  54519  (458) (−)-N-desmethylzopiclone 7,090 24 (5,960) Diazepam  12 notdetermined  (10)

[0112] Racemic and optically pure enantiomers of N-desmethylzopicloneclearly have affinity for the benzodiazepine site. Advantageously, andas discussed above, these compounds exhibited little activity at themuscarinic receptor.

Example 9 Oral Formulation

[0113] Suitable ingredients of a tablet dosage form of(+)-N-desmethylzopiclone are provided in Table 4. TABLE 4 ComponentQuantity per Tablet (mg) (+)-N-desmethylzopiclone  75 Lactose 125 CornStarch   5.0 Water (per thousand tablets)  30.0 ml* Magnesium Stearate  0.5

[0114] The active ingredient (i.e., (+)-N-desmethylzopiclone) is blendedwith the lactose until a uniform blend is formed. The smaller quantityof corn starch is blended with a suitable quantity of water to form acorn starch paste. This is then mixed with the uniform blend until auniform wet mass is formed. The remaining corn starch is added to theresulting wet mass and mixed until uniform granules are obtained. Thegranules are then screened through a suitable milling machine, using a{fraction (1/4)} inch stainless steel screen. The milled granules arethen dried in a suitable drying oven until the desired moisture contentis obtained. The dried granules are then milled through a suitablemilling machine using {fraction (1/4)} mesh stainless steel screen. Themagnesium stearate is then blended and the resulting mixture iscompressed into tablets of desired shape, thickness, hardness anddisintegration. Tablets may be coated by standard aqueous or nonaqueoustechniques.

[0115] Another tablet dosage formulation suitable for use with an activeingredient of the invention is provided by Table 5: TABLE 5 Quantity perTablet (mg) Component Formula A Formula B Formula C(+)-N-desmethylzopiclone 20 40 100 Lactose BP 134.5 114.5 309.0 StarchBP 30 30 60 Pregelatinized Maize Starch BP 15 15 30 Magnesium Stearate0.5 0.5 1.0 Compression Weight 200 200 500

[0116] The active ingredient is sieved and blended with lactose, starch,and pregelatinized maize starch. Suitable volumes of purified water areadded and the powders are granulated. After drying, the granules arescreened and blended with the magnesium stearate. The granules are thencompressed into tablets using punches.

[0117] Tablets of other strengths may be prepared by altering the ratioof active ingredient to pharmaceutically acceptable carrier, thecompression weight, or by using different punches.

Example 10 Oral Formulation

[0118] Capsules of (±)-N-desmethylzopiclone may be made using theingredients provided in Table 6: TABLE 6 Capsule Unit Dosage FormsQuantity per Capsule (mg) Formulation A B C (+)-N-desmethylzopiclone50.0 100.0 200.0 Lactose 48.5 148.5 48.5 Titanium Dioxide 0.5 0.5 0.5Magnesium Stearate 1.0 1.0 1.0 Fill Weight 100.0 250.0 250.0

[0119] The active ingredient (i.e., (±)-N-desmethylzopiclone) is sievedand blended with the excipients. The mixture is filled into suitablysized two-piece hard gelatin capsules using suitable machinery. Otherdoses may be prepared by altering the ratio of the active ingredient(e.g., (±)-N-desmethylzopiclone) and pharmaceutically acceptablecarrier, the fill weight and, if necessary, by changing the capsule sizeto suit.

Example 11 Oral Formulation

[0120] Hard gelatin capsules of (±)-N-desmethylzopiclone may be madeusing the ingredients provided in Table 7: TABLE 7 Hard Gelatin CapsuleUnit Dosage Forms 0.1 mg capsule 5 mg capsule 20 mg capsule Component(amount in mg) (amount in mg) (amount in mg) (±)-N-desmethyl- 0.1 5.020.0 zopiclone Microcrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized102.7 97.8 82.8 Starch Croscarmellose 7.0 7.0 7.0 Magnesium Stearate 0.20.2 0.2

[0121] The active ingredient is sieved and blended with the excipientslisted. The mixture is filled into suitably sized two-piece hard gelatincapsules using suitable machinery and methods well known in the art.See, e.g., Remington's Pharmaceutical Sciences, 16th or 18th Editions,each incorporated herein. Other doses may be prepared by altering thefill weight and, if necessary, changing the capsule size to suit. Any ofthe stable, non-lactose hard gelatin capsule formulations above may beformed.

Example 12 Oral Formulation

[0122] Compressed tablet formulations of (±)-N-desmethylzopiclone may bemade using the ingredients provided in Table 8: TABLE 8 CompressedTablet Formulations 0.1 mg tablet 5 mg tablet 20 mg tablet Component(amount in mg) (amount in mg) (amount in mg) (±)-N-desmethyl- 0.1 5.020.0 zopiclone Microcrystalline 90.0 90.0 90.0 Cellulose Pregelatinized102.7 97.8 82.8 Starch Croscarmellose 7.0 7.0 7.0 Magnesium Stearate 0.20.2 0.2

[0123] The active ingredient is sieved through a suitable sieve andblended with the non-lactose excipients until a uniform blend is formed.The dry blend is screened and blended with the magnesium stearate. Theresulting powder blend is then compressed into tablets of desired shapeand size. Tablets of other strengths may be prepared by altering theratio of the active ingredient (i.e., (±)-N-desmethylzopiclone) to theexcipient(s) or modifying the tablet weight.

[0124] The embodiments of the invention described above are intended tobe merely exemplary, and those skilled in the art will recognize, or beable to ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the invention andare encompassed by the following claims.

What is claimed is:
 1. A method of treating or preventing anxiety in a patient, which comprises administering to a patient suffering from anxiety a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 2. The method of claim 1, wherein the anxiety is acute anxiety.
 3. The method of claim 1 where in the anxiety is chronic anxiety
 4. The method of claim 1 where in the anxiety is general anxiety disorder.
 5. A method of treating or preventing a convulsive state in a patient, which comprises administering to a patient suffering from, or prone to suffer from, convulsions a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 6. The method of claim 5 wherein the convulsive state is epilepsy.
 7. A method of treating or preventing spasticity or acute muscle spasms in a patient, which comprises administering to a patient suffering from spasticity or acute muscle spasms a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 8. A method of treating or preventing an affective disorder in a patient, which comprises administering to a patient suffering from an affective disorder a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 9. The method of claim 8, wherein the affective disorder is depression.
 10. The method of claim 8, wherein the affective disorder is attention deficit disorder or attention deficit disorder with hyperactivity.
 11. A method of treating or preventing a behavioral disorder in a patient, which comprises administering to a patient suffering from a behavioral disorder a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 12. A method of treating or preventing schizophrenic disorder in a patient, which comprises administering to a patient suffering from schizophrenic disorder a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 13. A method of treating or preventing aggressive behavior in a patient, which comprises administering to a patient suffering from aggressive behavior a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 14. A method of treating or preventing alcohol or drug addiction in a patient, which comprises administering to a patient suffering from alcohol or drug addiction a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 15. A method of treating or preventing abnormal plasma hormone levels in a patient, which comprises administering to a patient suffering from abnormal plasma hormone levels a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 16. The method of claim 15, wherein the abnormal plasma hormone level is endocrine.
 17. A method of treating or preventing a sleep disorder in a patient, which comprises administering to a patient suffering from a sleep disorder a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 18. The method of claim 17, wherein the sleep disorder is insomnia.
 19. A method of treating or preventing a disease or condition or symptom thereof in a patient affected by the modulation of one or more central or peripheral benzodiazepine receptors, which comprises administering to said patient a therapeutically or prophylactically effective amount of N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 20. The method of claim 1, 5, 7, 8, 11-15, 17, or 19 wherein the N-desmethylzopiclone is racemic.
 21. The method of claim 1, 5, 7, 8, 11-15, 17, or 19 wherein the N-desmethylzopiclone is (+)-N-desmethylzopiclone, substantially free of its (−) enantiomer.
 22. The method of claim 1, 5, 7, 8, 11-15, 17 or 19 wherein the N-desmethylzopiclone is (−)-N-desmethylzopiclone, substantially free of its (+) enantiomer.
 23. The method of claim 21 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount N-desmethylzopiclone.
 24. The method of claim 22 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.
 25. The method of claim 23 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.
 26. The method of claim 24 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.
 27. The method of claim 25 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.
 28. The method of claim 26 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.
 29. The method of claim 1, 5, 7, 8, 11-15, 17, or 19 wherein the patient is human.
 30. The method of claim 1, 5, 7, 8, 11-15, 17, or 19 wherein the therapeutically or prophylactically effective amount of N-desmethylzopiclone or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof is from about 0.1 mg to about 500 mg.
 31. The method of claim 30 wherein the therapeutically or prophylactically effective amount of N-desmethylzopiclone or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof is from about 0.5 mg to about 250 mg.
 32. The method of claim 31 wherein the therapeutically or prophylactically effective amount of N-desmethylzopiclone or pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof is from about 1 mg to about 200 mg.
 33. A pharmaceutical composition comprising N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 34. The pharmaceutical composition of claim 33 wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
 35. The pharmaceutical composition of claim 33 wherein the N-desmethylzopiclone is racemic.
 36. The pharmaceutical composition of claim 33 wherein the N-desmethylzopiclone is (+)-N-desmethylzopiclone, substantially free of its (−) enantiomer.
 37. The pharmaceutical composition of claim 33 wherein the N-desmethylzopiclone is optically pure (−)-N-desmethylzopiclone, substantially free of its (+) enantiomer.
 38. The pharmaceutical composition of claim 36 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.
 39. The pharmaceutical composition of claim 37 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.
 40. The pharmaceutical composition of claim 38 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.
 41. The pharmaceutical composition of claim 39 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.
 42. The pharmaceutical composition of claim 40 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.
 43. The pharmaceutical composition of claim 41 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.
 44. The pharmaceutical composition of claim 33 wherein said pharmaceutical composition is suitable for parenteral, oral, topical, transdermal, or mucosal administration to a patient.
 45. The pharmaceutical composition of claim 44 wherein said pharmaceutical composition is suitable for oral administration to a patient.
 46. An individual dosage form of N-desmethylzopiclone which comprises N-desmethylzopiclone, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 47. The dosage form of claim 46 wherein said dosage form further comprises a pharmaceutically acceptable carrier.
 48. The dosage form of claim 46 wherein the N-desmethylzopiclone is racemic.
 49. The dosage form of claim 46 wherein the N-desmethylzopiclone is (+)-N-desmethylzopiclone, substantially free of its (−) enantiomer.
 50. The dosage form of claim 46 wherein the N-desmethylzopiclone is optically pure (−)-N-desmethylzopiclone, substantially free of its (+) enantiomer.
 51. The dosage form of claim 49 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.
 52. The dosage form of claim 50 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 90% by weight of the total amount of N-desmethylzopiclone.
 53. The method of claim 51 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.
 54. The method of claim 52 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 95% by weight of the total amount of N-desmethylzopiclone.
 55. The method of claim 53 wherein the amount of (+)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.
 56. The method of claim 54 wherein the amount of (−)-N-desmethylzopiclone, or a pharmaceutically acceptable salt thereof, is greater than about 99% by weight of the total amount of N-desmethylzopiclone.
 57. The dosage form of claim 46 wherein said dosage form is suitable for parenteral, oral, topical, transdermal, or mucosal administration to a patient.
 58. The dosage form of claim 57 wherein said dosage form is a tablet, caplet, or capsule.
 59. The dosage form of claim 46 wherein said dosage form comprises from about 0.1 mg to about 500 mg of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 60. The dosage form of claim 59 wherein said dosage form comprises from about 0.5 mg to about 250 mg of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 61. The dosage form of claim 60 wherein said dosage form comprises from about 1 mg to about 200 mg of N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof.
 62. A method of preparing N-desmethylzopiclone which comprises contacting zopiclone with an azodicarboxylate under conditions sufficient to form a product and hydrolyzing the product under mild conditions.
 63. The method of claim 62 wherein the azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, and di-trichloromethyl azodicarboxylate.
 64. The method of claim 63 wherein the azodicarboxylate is diethyl azodicarboxylate.
 65. A method of preparing racemic N-desmethylzopiclone which comprises contacting racemic zopiclone with a-chloroethyl chloroformate to form a mixture and refluxing said mixture in methanol.
 66. A method of preparing (+)-N-desmethyl zopiclone which comprises contacting (+)-zopiclone with a-chloroethyl chloroformate to form a mixture and refluxing said mixture in methanol.
 67. A method of preparing (−)-N-desmethylzopiclone which comprises contacting (−)-zopiclone with α-chloroethyl chloroformate to form a mixture and refluxing said mixture in methanol.
 68. A method of increasing the optical purity of zopiclone or desmethylzopiclone which comprises contacting zopiclone or desmethylzopiclone with L-N-benzyloxycarbonyl phenyl alanine in a water and ethanol solvent system, and isolating optically enriched zopiclone or desmethylzopiclone. 